TXNRD2

Chr 22AR

thioredoxin reductase 2

Also known as: GCCD5, SELZ, TR, TR-BETA, TR3, TRXR2, TXNR2

NCBI Gene: 10587 ENSG00000184470 UniProt: Q9NNW7 OMIM: 606448

The protein encoded by TXNRD2 is a mitochondrial selenoenzyme that reduces thioredoxin and maintains mitochondrial redox homeostasis by scavenging reactive oxygen species. Mutations cause glucocorticoid deficiency 5, inherited in an autosomal recessive pattern. The gene shows very low constraint against loss-of-function variants (pLI near 0), which is consistent with recessive inheritance where heterozygous carriers are typically unaffected.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene belongs to the pyridine nucleotide-disulfide oxidoreductase family, and is a member of the thioredoxin (Trx) system. Three thioredoxin reductase (TrxR) isozymes are found in mammals. TrxRs are selenocysteine-containing flavoenzymes, which reduce thioredoxins, as well as other substrates, and play a key role in redox homoeostasis. This gene encodes a mitochondrial form important for scavenging reactive oxygen species in mitochondria. It functions as a homodimer containing FAD, and selenocysteine (Sec) at the active site. Sec is encoded by UGA codon that normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, the Sec insertion sequence (SECIS) element, which is necessary for the recognition of UGA as a Sec codon rather than as a stop signal. Alternatively spliced transcript variants encoding different isoforms, including a few localized in the cytosol and some lacking the C-terminal Sec residue, have been found for this gene. [provided by RefSeq, Jun 2017]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.991 OMIM phenotype

Clinical Summary— TXNRD2

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

184 VUS of 397 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TXNRD2

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.99LOEUF

pLI 0.000

Z-score 1.60

OE 0.69 (0.49–0.99)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.64Z-score

OE missense 0.90 (0.82–0.99)

296 obs / 328.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.69 (0.49–0.99)

0≤0.351.4

Missense OE?0.90 (0.82–0.99)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 21 / 30.5Missense obs/exp: 296 / 328.5Syn Z: -0.60

This gene — mechanism propensity

0.6452th %ile

GOF

0.6736th %ile

LOF

0.3647th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

397 submitted variants in ClinVar

ClinVar

Classification Summary

VUS184

Likely Benign168

Benign30

Conflicting8

184

VUS

168

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	19	145	17	3	184
Likely Benign	0	5	66	97	168
Benign	0	1	29	0	30
Conflicting	—				8
Total	19	151	112	100	390

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

91 pathogenic / likely-pathogenic (of 97) ClinVar copy-number / structural variants overlap TXNRD2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →